The latest breakthroughs in treatment for genetic diseases

This European website, initiated and developed by CSL Behring, has two separate sections with the aim to provide information on haemophilia for an international audience, either to European healthcare professionals or to the general public.*

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In the last decade, gene therapy has become a reality for many patients with genetic diseases and chronic conditions.^1-6

ABOUT GENE THERAPY

VIEW GENE THERAPY IN HAEMOPHILIA Understanding the Principles of Gene Therapies

The goal of gene therapy is to achieve durable expression of a transgene - or therapeutic gene - which replaces a defective or mal-adaptive gene such that symptoms of a genetic disease are ameliorated, or even cured, all while minimizing adverse risks.^7,8 Gene therapies can also be used to promote the production of therapeutic proteins or to induce cell death. These latter applications are useful for patients with non-genetic diseases such as cancers or infections.⁷

Genetic therapy research began more than 50 years ago⁹ and in the 1990s, clinical investigation focused on its application among patients with a broad range of indications. To date, more than 2500 clinical studies have been initiated¹ and several adeno-associated viral (AAV) vector gene therapies are approved by the European Medicines Agency (EMA) or by the US Food and Drug Administration (FDA).^1-6 The FDA predicts, based on the current pipeline and the success rates of trials, that they will be approving 10-20 cell-and gene-based therapies every year by 2025.¹⁰

VIEW GENE THERAPY IN HAEMOPHILIA Understanding the Principles of Gene Therapies

Research Progress

50+

Years of ongoing research into gene therapy⁹

2,5k+

Active clinical trials in genetic therapy research¹¹

24%

of active clinical trials are of AAV vector-based technologies¹²

5+

AAV vector-based gene therapies approved by the EMA or the FDA^2-6

There are different methods of gene therapy application, such as in vivo gene therapy, ex vivo gene therapy and gene editing.

in vivo Gene Therapy

First approved for therapeutic use in 2012 by the EMA,⁷ a viral vector comprising a transgene and its promoter is delivered to physiologically relevant target tissue(s).¹³ The most common method of transgene delivery is with an AAV vector.⁷ Treatments which use this approach have been approved for retinal dystrophy² and spinal muscular atrophy.³

By 2023, the first gene therapies were approved for the treatment of haemophilia A and B in Europe and in the USA. The therapeutic genes are delivered with an AAV vector.^4-6,14,15

ex vivo Gene Therapy

First approved for therapeutic use in 2016 by the EMA, this approach involves extracting cells from a patient, transducing the cells with a gene of interest using a viral vector, such as a g-retroviral vector, and returning the cells carrying the transgene to the patient.⁷ This type of cell therapy has been approved for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID),⁷ melanoma,¹ acute lymphoblastic leukaemia, non-Hodgkin lymphoma¹ and b-thalassemia.¹⁶

Gene editing

The goal of gene editing is to make changes to original DNA, by replacing, inserting or knocking down the regions of a patient’s genome associated with disease.¹ This is achieved by exploiting the natural cellular response to DNA breaks, like the tool used by bacterial immune systems, clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9.¹⁶ In 2020, the Nobel Prize in Chemistry was awarded to Drs. Emmanuelle Charpentier and Jennifer Doudna for their work on CRISPR-Cas9.¹⁷ Although no products have been commercially approved for therapeutic use in humans, clinical trials using gene editing technologies have recruited patients with Leber congenital amaurosis¹⁸ or cancer.^16,19

THE ROLE OF VIRAL VECTORS

ABOUT AAV-BASED GENE THERAPY Many gene therapy technologies use a viral vector as the transfer vehicle for the transgene of interest.

Viral vectors are the most commonly utilised agents for gene therapy¹¹ owing to their efficient ability to deliver many copies of therapeutic genes to host cells.⁷ There have been extensive trials using multiple types of vectors.^1,11 The factors which determine the type of vector to use include the size of the transgene and whether you are using an in vivo or ex vivo approach.¹

ABOUT AAV-BASED GENE THERAPY Many gene therapy technologies use a viral vector as the transfer vehicle for the transgene of interest.

Here are some of the main types of viral vectors gene therapies use.

Scientists have been exploring gene therapy as a potential treatment approach for well over 50 years.⁹ In the past decade several AAV vector products have been approved by the EMA or by the FDA.^2-6 Gene therapies are currently being researched in many clinical trials for a variety of indications^1,11 including various genetic disorders, such as haemophilia A²¹ and B²².

1986

First Successful Gene Therapy in Mammalian Cells

Mouse cells which had a defective gene with point mutations and deletions were corrected by plasmid injections.^17,23

1990

First Gene Therapy Trial in Humans

A paediatric patient with adenosine deaminase (ADA)-deficient severe combined immunodeficiency disease (SCID) received an ADA transgene delivered by a retroviral vector.²⁴

2005

First AAV Vector Gene Therapy Trial in Haemophilia B

A canine model for haemophilia B was used as a proof-of-concept that intramuscular injections allowed for in vivo delivery of a transgene using AAV vectors.²⁵

2012

First Gene Therapies Approved by the EMA

The EMA approved a gene therapy for patients with a lipoprotein lipase deficiency.²⁶

2015

First AAV Vector Human Gene Therapy Trial in Haemophilia A

A phase I/II, dose-escalation trial of an intravenous AAV vector infusion for patients with severe haemophilia A found durable and sustained normalization of factor VIII activity.²¹

2017

First Gene Therapy is Approved by the FDA

The FDA approved a gene therapy for paediatric patients and young adults with acute lymphoblastic leukaemia.²⁷

2018

First AAV Vector Gene Therapy is Approved by the EMA

The EMA approved an AAV-based gene therapy for inherited retinal dystrophy.²

2020

The EMA Approves a Second AAV Vector Gene Therapy

The EMA approved a second AAV-based gene therapy for spinal muscular atrophy.³

2022-2023

First Gene Therapies for Haemophilia Approved in Europe and in the USA

In 2022 and 2023, the first adeno-associated virus vector-based gene therapies for the treatment of adults with haemophilia A and B were approved in Europe and in the USA.^4-6,14,15

Today

Gene Therapy Research is Ongoing

Among all ongoing clinical trials of gene therapies, 24% are using AAV vector applications for multiple genetic disorders and chronic conditions.^1,11,12

Available Treatments for Haemophilia

How have treatment options for patients with haemophilia advanced over the years and what options are currently available?

Gene Therapy for Haemophilia

Learn about what makes haemophilia the optimal candidate for a gene therapy.

References

Anguela XM, High KA. Entering the modern era of gene therapy. Annu Rev Med. 2019;70:273-288.
European Medicines Agency. Luxturna. https://www.ema.europa.eu/en/medicines/human/EPAR/luxturna. Accessed November 5, 2021.
European Medicines Agency. Zolgensma. https://www.ema.europa.eu/en/medicines/human/EPAR/zolgensma. Accessed November 5, 2021.
Food and Drug Administration. Approved Cellular and Gene Therapy Products. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products. Accessed September 5, 2023.
European Medicines Agency (EMA). Roctavian. https://www.ema.europa.eu/en/medicines/human/EPAR/roctavian-0. Accessed January 28, 2023.
European Medicines Agency (EMA). Hemgenix. https://www.ema.europa.eu/en/medicines/human/EPAR/hemgenix. Accessed July 14, 2023.
High KA, Roncarolo MG. Gene therapy. N Engl J Med. 2019;381(5):455-464.
McCain J. The future of gene therapy. Biotechnol Healthc. 2005;2(3):52-54,56-60.
Friedmann T, Roblin R. Gene therapy for human genetic disease? Science. 1972;175(4025):949-955.
Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies. [press release]. Silver Spring, Maryland, USA: US Food and Drug Administration (FDA). https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics. Published January 15, 2019. Accessed November 5, 2021.
Ghosh S, Brown AM, Jenkins C, Campbell K. Viral vector systems for gene therapy: a comprehensive literature review of progress and biosafety challenges. Appl Biosaf. 2020;25(1):7-18.
Food and Drug Administration (FDA) Cellular, Tissue, and Gene Therapies Advisory Committee Meeting #70. Toxicity Risks of Adeno-associated Virus (AAV) Vectors for Gene Therapy (GT). Published September 2021.
Wang D, Tai PWL, Gao G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov. 2019;18(5):358-378.
FDA Approves First Gene Therapy to Treat Adults with Hemophilia B [press release]. Silver Spring, Maryland, USA: US Food and Drug Administration (FDA). https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treat-adults-hemophilia-b. November 22, 2022. Accessed January 5, 2023.
First gene therapy to treat severe haemophilia A [press release]. London, England: European Medicines Agency (EMA). Published June 24, 2022. First gene therapy to treat severe haemophilia A | European Medicines Agency (europa.eu). Accessed June 24, 2022.
Bak RO, Gomez-Ospina N, Porteus MH, Gene editing on center stage. Trends Genet. 2018;34(8):600-611.
Ledford H, Callaway E. Pioneers of CRISPR gene editing win chemistry Nobel. Nature. 2020;586:346-3475.
ClinicalTrials.gov. Single Ascending Dose Study in Participants With LCA10. https://clinicaltrials.gov/ct2/show/NCT03872479. Accessed January 2, 2022.
Zhan T, Rindtorff N, Betge J, Ebert MP, Boutros M. CRISPR/Cas9 for cancer research and therapy. Semin Cancer Biol. 2019;55:106-119.
Bulcha JT, Wang Y, Ma H, et al. Viral vector platforms within the gene therapy landscape. Signal Transduct Target Ther. 2021;6(1):53.
Rangarajan S, Walsh L, Lester W, et al. AAV5-Factor VII gene transfer in severe hemophilia A. N Engl J Med. 2017;377(26):2519-2530.
Nathwani AC, Reiss UM, Tuddenham EGD, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014;371:1994-2004.
Thomas KR, Folger KR, Capecchi MR. High frequency targeting of genes to specific sites in the mammalian genome. Cell. 1986;44:419-428.
Muul LM, Tuschong LM, Soenen SL, et al. Persistence and expression of the adenosine deaminase gene for 12 years and immune reaction to gene transfer components: long-term results of the first clinical gene therapy trial. Blood. 2003;101(7):2563-2569.
Arruda V, Stedman H, Jian H, et al. Correction of hemophilia B phenotype by novel method of regional intravenous delivery of AAV vector to skeletal muscle of hemophilia B dogs. Mol Ther. 2005;11:S233.
European Medicines Agency recommends first gene therapy for approval [press release]. London, England: European Medicines Agency (EMA). https://www.ema.europa.eu/en/news/european-medicines-agency-recommends-first-gene-therapy-approval. Published July 20, 2012. Accessed November 5, 2021.
FDA approval brings first gene therapy to the United States [press release]. Silver Spring, Maryland, USA: US Food and Drug Administration (FDA). https://www.fda.gov/news-events/press-announcements/fda-approval-brings-first-gene-therapy-united-states. Published August 30, 2017. Accessed November 5, 2021.

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The Latest Breakthroughs in Treatment for Genetic Diseases

Understanding the Principles of Gene Therapies

Current Progress in Genetic Therapy Research